1. Field of the Invention
This invention is directed to novel compositions for embolizing blood vessels which are particularly suited for treating aneurysms, arteriovenous malformations (AVMs) at high flow fistulas and embolizing blood vessels.
In one embodiment, the compositions of this invention comprise a biocompatible polymer, a biocompatible solvent and a biocompatible contrast agent wherein the viscosity of the composition is at least about 150 cSt and preferably at least about 200 cSt at 40xc2x0 C.
2. References
The following publications are cited in this application as superscript numbers:
Mandai, et al., xe2x80x9cDirect Thrombosis of Aneurysms with Cellulose Acetate Polymerxe2x80x9d, J. Neurosurg., 77:497-500 (1992)
Kinugasa, et al., xe2x80x9cDirect Thrombosis of Aneurysms with Cellulose Acetate Polymerxe2x80x9d, J: Neurosurg., 77:501-507 (1992)
Casarett and Doull""s Toxicology, Amdur et al., Editors, Pergamon Press, New York, pp. 661-664 (1975)
Greff, et al., U.S. Pat. No. 5,667,767 for xe2x80x9cNovel Compositions for Use in Embolizing Blood Vesselsxe2x80x9d, issued on Sep. 16, 1997
Greff, et al., U.S. Pat. No. 5,580,568 for xe2x80x9cCellulose Diacetate Compositions for Use in Embolizing Blood Vesselsxe2x80x9d, issued on Dec. 3, 1996
Kinugasa, et al., xe2x80x9cEarly Treatment of Subarachnoid Hemorrhage After Preventing Rerupture of an Aneurysmxe2x80x9d, J Neurosurg., 83:34-41 (1995)
Kinugasa, et al., xe2x80x9cProphylactic Thrombosis to Prevent New Bleeding and to Delay Aneurysm Surgeryxe2x80x9d, Neurosurg., 36:661 (1995)
Taki, et al., xe2x80x9cSelection and Combination of Various Endovascular Techniques in the Treatment of Giant Aneurysmsxe2x80x9d, J. Neurosurg., 77:37-42 (1992)
Evans, et al., U.S. patent application Ser. No. 08/655,822 for xe2x80x9cNovel Compositions for Use in Embolizing Blood Vesselsxe2x80x9d, filed May 31, 1996.
Dunn, et al., U.S. Pat. No. 4,938,763 for xe2x80x9cBiodegradable In-Situ Forming Implants and Methods of Producing Samexe2x80x9d, issued Jul. 3, 1990
All of the above references are herein incorporated by reference in their entirety to the same extent as if each individual reference was specifically and individually indicated to be incorporated herein by reference in its entirety.
3. State of the Art
Embolization of blood vessels is conducted for a variety of purposes including the treatment of tumors, the treatment of lesions such as aneurysms, uncontrolled bleeding and the like.
Embolization of blood vessels is preferably accomplished via catheter techniques which permit the selective placement of the catheter at the vascular site to be embolized. In this regard, recent advancements in catheter technology as well as in angiography now permit neuroendovascular intervention including the treatment of otherwise inoperable lesions. Specifically, development of microcatheters and guide wires capable of providing access to vessels as small as 1 mm in diameter allows for the endovascular treatment of many lesions.
Embolizing compositions (embolic compositions) heretofore disclosed in the art include those comprising a biocompatible polymer, a biocompatible solvent and a contrast agent which allowed visualization of the in vivo delivery of the composition via fluoroscopy.1-8 Such compositions typically contain no more than about 8 weight percent of biocompatible polymer based on the weight of the total composition.
Notwithstanding the benefits associated with the use of such embolic compositions in treating aneurysms and other vascular disorders, in vivo these compositions formed coherent masses which often suffer from solidification and formation of a coherent mass distal from the point of ejection from the catheter. That is to say that upon ejection of the embolic composition in a vascular site, the coherent mass subsequently formed was often distal and not proximate the ejection port of the catheter. Moreover, upon solidification, the solid mass formed was often linear in shape (i.e., having a xe2x80x9cstring shapexe2x80x9d).
In many circumstances, a contiguous or ball shape precipitate formed at the ejection port is desired (e.g., to fill an aneurysm). Distal solidification of a string shape precipitate makes site specific delivery of the solid mass in the vasculature difficult. As is apparent, site specific delivery of the solid mass is essential for treatment of vascular disorders such as aneurysms. Solidification at points distal to the ejection port, as is common in string shape precipitates, can result in the solid mass forming not in the aneurysm sac but in the artery attendant the aneurysm. Such a string shape precipitate is more prone to fragmentation which can lead to embolization of this artery and possible incapacitation or death of the patient. Moreover, such fragmentation can lead to particles or fragments being xe2x80x9cwashedxe2x80x9d downstream and lodging at undesired locations in the vasculature.
This invention is based, in part, on the discovery that the formation of a solid non-migratory mass having a substantially contiguous or xe2x80x9cballxe2x80x9d shape can be achieved by use of embolic compositions comprising a biocompatible polymer, a biocompatible solvent and optionally a contrast agent wherein the composition has a viscosity of at least about 150 cSt at 40xc2x0 C. The use of such high viscosity embolic compositions was heretofore not preferred in view of the fact that the viscosity of these compositions is significantly higher than those containing 8 weight percent polymer thereby rendering it difficult to employ conventional delivery means (e.g., syringe) for use in combination with the catheter for the controlled delivery of these compositions in vivo.
However, delivery means such as the threaded syringes described, for example, in U.S. Provisional Patent Application Serial Nos. 60/135,289 and 60/135,287, entitled xe2x80x9cTHREADED SYRINGExe2x80x9d under Attorney Docket No. 018413-194 and entitled xe2x80x9cSCREW SYRINGE WITH FORCE RELEASE MECHANISMxe2x80x9d under Attorney Docket No. 018413-198, both of which were filed on May 21, 1999, now renders the use of these highly viscous compositions practical. Both of these applications are incorporated herein by reference in their entirety.
This invention is directed to the novel and unexpected discovery that the use of embolic compositions comprising a viscosity of at least about 150 cSt at 40xc2x0 C. provides for the in vivo formation of a solid, non-migratory mass which mass is substantially contiguous in shape.
Without being limited to any theory, it is now believed that embolic compositions having such a high viscosity permit more rapid and consistent solidification in vivo thereby rendering the solid mass formed non-migratory and substantially contiguous in shape. It is further believed that the rapid and consistent solidification in vivo arises at least in part from the high viscosity of these compositions which renders migration from the ejection port of the catheter at the vascular site more difficult.
Accordingly, in one of its composition aspects, this invention is directed to a composition comprising a biocompatible polymer, a biocompatible contrast agent, and a biocompatible solvent which solubilizes said biocompatible polymer
wherein sufficient amounts of said polymer are employed in said composition such that, upon delivery to a vascular site, a polymer precipitate forms which embolizes said vasculare site; and
further wherein the viscosity of said composition is at least about 150 cSt at 40xc2x0 C.
In another of its composition aspects, this invention is directed to a composition comprising:
(a) a biocompatible polymer at a concentration of from about 2 to 50 weight percent;
(b) a biocompatible contrast agent at a concentration of from about 10 to about 40 weight percent; and
(c) a biocompatible solvent from about 10 to 88 weight percent
wherein the weight percent of the biocompatible polymer, contrast agent and biocompatible solvent is based on the total weight of the complete composition; and
further wherein the composition has a viscosity of at least about 150 and more preferably at least about 200 cSt at 40xc2x0 C.
Preferably in this particular composition, the concentration of the polymer ranges from 6 to 50 weight percent and more preferably 8 to 30 weight percent.
In another of its composition aspects, this invention is directed to a composition comprising:
(a) a biocompatible polymer at a concentration of from about 12 to 50 weight percent;
(b) a biocompatible contrast agent at a concentration of from about 10 to about 40 weight percent; and
(c) a biocompatible solvent from about 10 to 78 weight percent
wherein the weight percent of the biocompatible polymer, contrast agent and biocompatible solvent is based on the total weight of the complete composition and
further wherein the composition has a viscosity of at least about 150, preferably at least about 200 and more preferably at least 500 cSt at 40xc2x0 C.
Preferably the viscosity ranges from about 200 to 40,000 cSt at 40xc2x0 C., more preferably from about 500 to 40,000 cSt at 40xc2x0 C. In another embodiment, the viscosity ranges from about 500 to 5000 cSt at 40xc2x0 C.
In one of its method aspects, this invention is directed to a method for enhancing the formation of a solid, non-migratory coherent mass at a selected vascular site of a mammal which method comprises:
(a) placing a delivery device having an ejection port at a selected vascular site in a mammal;
(b) delivering through the ejection port of the delivery device a composition comprising a biocompatible polymer, a biocompatible solvent and optionally a contrast agent wherein the viscosity of the composition is at least about 150 cSt at 40xc2x0 C.
Preferably the composition delivered in (b) above comprises a biocompatible polymer, a biocompatible contrast agent and a biocompatible solvent which solubilizes the biocompatible polymer wherein the weight percents of the biocompatible polymer, contrast agent and biocompatible solvent are based on the total weight of the complete composition; further wherein sufficient amounts of said polymer are employed in said composition such that, upon delivery to a vascular site, a polymer precipitate forms which embolizes said vasculare site; and still further wherein the viscosity of said composition is at least about 150 cSt at 40xc2x0 C.
More preferably, the composition delivered in (b) above comprises a biocompatible polymer at a concentration of from about 2 to 50 weight percent, a biocompatible contrast agent at a concentration of from about 10 to about 40 weight percent, and a biocompatible solvent from about 10 to 88 weight percent wherein the weight percent of the biocompatible polymer, contrast agent and biocompatible solvent is based on the total weight of the complete composition and further wherein the composition has a viscosity of at least about 150 and more preferably at least about 200 cSt at 40xc2x0 C.
Optionally, prior to the delivering aspect of (b) above, blood flow through the vascular site can be attenuated by insertion of a blood flow attenuating device immediately upstream the ejection port. Such a blood flow attenuating device is preferably an inflatable microballoon which permits both normal and attenuated blood flow depending upon whether the microballoon is deflated or inflated.
The contrast agent is either a water soluble contrast agent or a water insoluble contrast agent. Preferably, the water insoluble contrast agent is a biocompatible material selected from the group consisting of barium sulfate, tantalum powder and tantalum oxide.
In still a further preferred embodiment, the biocompatible solvent is dimethylsulfoxide (DMSO), ethanol, ethyl lactate or acetone.